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Note that the study suggests that based on the dose-response relationship, further clinical trials of vericiguat are needed to determine the potential role of this drug for patients with worsening chronic heart failure.

While the drug did not meet its primary endpoint of significant reduction in N-terminal pro-B type natriuretic peptide (NT-proBNP) levels, secondary analyses found a potential dose-response relationship for patients receiving higher doses of the drug (P<0.02), reported Mihai Gheorghiade, MD, of Northwestern University in Chicago, and colleagues at the American Heart Association (AHA) meeting.

Pooled results from the three highest doses of vericiguat (2.5 mg, 5 mg, and 10 mg) were associated with a 33.1% reduction in NT-proBNP levels after 12 weeks of treatment, but the difference was not statistically significant versus placebo (difference -0.122, 90% CI -0.32-0.07, ratio of geometric means 0.885, P=0.15).

Results from the SOCRATES-REDUCED randomized trial was published simultaneously in JAMA.

While not involved with this study, Christoper Newton-Cheh, MD, MPH, of Massachusetts General Hospital in Boston told MedPage Today this was an important area of research, as many heart failure patients on standard of care drugs continue to experience symptoms, hospitalization, and even death.

"There's a lot of enthusiasm for trying to identify drugs that target this pathway," he said. "There's definitely a big gap if you consider where our current therapies are for patients with heart failure with reduced ejection fraction."

Vericiguat is a soluble guanylate cyclase stimulator that "offer a novel approach for addressing the relative cGMPdeficit in worsening chronic HF. These agents modulate sGC in a nitric oxide–independent manner, mimicking nitric oxide and restoring downstream cGMPsignaling," the authors explained.

The vericiguat group received maximal doses of either 1.25 mg, 2.5 mg, 5 mg or 10 mg, with the two highest doses of the drug titrated over the course of the study.

Exploratory analyses found a 41.0% reduction in the 10-mg vericiguat group compared to the 2.5-mg group, which was statistically significant (ratio of geometric means 0.779, P=0.048).

Christopher O'Connor, MD, of Inova Heart and Vascular Institute in Falls Church, Va.,, said that while the important secondary endpoints met nominal statistical significance, it was good that they were all trending in the same direction.

"I think it's possible there's still another dose that's higher that could be more effective, because they didn't see a lot of negative safety signals," O'Connor, who was not involved with the study, told MedPage Today.

Overall, the portion of adverse events was slightly higher in the vericiguat group, with 77.2% among patients taking placebo and up to 78.9% (in the 2.5-mg group). Treatment-emergent hypotension and treatment-emergent syncope were the most common in the 10-mg vericiguat group (15.4% and 4.4%, respectively).

"We were pleasantly surprised that there were no clinical adverse effects on blood pressure, heart rate, renal function or troponin," said Gheorghiade at a AHA press conference.

Though the study was not powered to detect clinical events, the rate of composite cardiovascular death or heart failure hospitalization was lower in the vericiguat group (11% to 18.7% across treatment groups) compared to placebo (19.6%). All-cause mortality was lower in the 10-mg vericiguat group compared to placebo (6.5% versus 4.4%, respectively).

This dose-finding phase II study had 351 patients (77.0%) completing treatment with the study drug. Baseline characteristics of the four vericiguat groups and the placebo groups were relatively similar, although there were higher median NT-proBNP levels in the placebo and 1.25 vericiguat groups.

Newton-Cheh said the fact that the "chance difference" in median proBNP levels between the two groups may have had an impact on the results.

"It's actually not uncommon that when the values that are higher at baseline, it's easier to see a decrease in those values over the course of the study," he said. "This could have hurt the current study because it would've acted against potential effect of the drug."

The authors concluded that based on the dose-response relationship, further clinical trials of vericiguat are needed to determine the potential role of this drug for patients with worsening chronic heart failure.

O'Connor pointed out that while the study authors were conservative in their interpretations, there has been a resurgence of interest in these types of drugs because of positive results from other studies.

"Novel pathways are very exciting for the community and I think this has significant potential," he concluded.

The SOCRATES-REDUCED trial was funded by affiliates of Bayer and Merck Sharp & Dohme, a subsidiary of Merck. Some co-authors are employees of Bayer.

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